Use of glucocorticoid receptor antagonist and somatostatin analogues to treat acth-secreting tumors

Abstract

Methods, compositions, and pharmaceutical formulations are provided for treatment of ACTH secreting tumors.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application is a U.S. National Phase Continuation Application of PCT / US2016 / 019646, filed Feb. 25, 2016, which claims priority to U.S. Provisional Application No. 62 / 127,153, filed Mar. 2, 2015, the contents of which are hereby incorporated in the entirety for all purposes.BACKGROUND OF THE INVENTION

[0002] Adrenocorticotropic hormone (ACTH) is a polypeptide-based hormone that is normally produced and secreted by the anterior pituitary gland. ACTH stimulates secretion of cortisol and other glucocorticoids by specialized cells of the adrenal cortex. In healthy mammals, ACTH secretion is tightly regulated. ACTH secretion can be positively regulated by corticotropin releasing hormone (CRH), which is released by the hypothalamus. ACTH secretion can be negatively regulated by cortisol and other glucocorticoids.

[0003] Aberrant ACTH-levels can lead to a wide variety of undesirable physiological conditions. For example, excess ACTH levels can ...

Examples

example 1

of a Subject with an Ectopic ACTH-Secreting Tumor

[0188]A human patient with an ectopic ACTH-secreting pancreatic neuroendocrine tumor metastatic to liver gastrinoma presented with symptoms of ectopic Cushing's Syndrome. The patient was treated with the maximum recommended dose of octreotide long-acting release (LAR), a partial biochemical response was noted (ACTH decreased from 517 pg / mL (113.7 pmol / L) to 345 pg / mL (75.9 pmol / L)), but the Cushing's symptoms were not controlled. After three months of therapy with octreotide LAR, the patient was enrolled in a 24-week, phase 3 clinical trial of mifepristone (MIFE) for inoperable hypercortisolemia.

[0189]Prior to the start of MIFE, baseline urinary-free cortisol (UFC) was 2250 mcg / 24 hours (6207 nmol / 24 hours) and ACTH was 345 pg / mL (75.9 pmol / L). Late-night salivary cortisol (1.71 mcg / dL (47.2 nmol / L)) and serum cortisol (46 mcg / dL (1256 nmol / L)) were also elevated (Table 1). At the time of enrollment, the patient had overtly cushingoid...

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application is a U.S. National Phase Continuation Application of PCT / US2016 / 019646, filed Feb. 25, 2016, which claims priority to U.S. Provisional Application No. 62 / 127,153, filed Mar. 2, 2015, the contents of which are hereby incorporated in the entirety for all purposes.BACKGROUND OF THE INVENTION

[0002] Adrenocorticotropic hormone (ACTH) is a polypeptide-based hormone that is normally produced and secreted by the anterior pituitary gland. ACTH stimulates secretion of cortisol and other glucocorticoids by specialized cells of the adrenal cortex. In healthy mammals, ACTH secretion is tightly regulated. ACTH secretion can be positively regulated by corticotropin releasing hormone (CRH), which is released by the hypothalamus. ACTH secretion can be negatively regulated by cortisol and other glucocorticoids.

[0003] Aberrant ACTH-levels can lead to a wide variety of undesirable physiological conditions. For example, excess ACTH levels can ...

Examples

example 1

of a Subject with an Ectopic ACTH-Secreting Tumor

[0188]A human patient with an ectopic ACTH-secreting pancreatic neuroendocrine tumor metastatic to liver gastrinoma presented with symptoms of ectopic Cushing's Syndrome. The patient was treated with the maximum recommended dose of octreotide long-acting release (LAR), a partial biochemical response was noted (ACTH decreased from 517 pg / mL (113.7 pmol / L) to 345 pg / mL (75.9 pmol / L)), but the Cushing's symptoms were not controlled. After three months of therapy with octreotide LAR, the patient was enrolled in a 24-week, phase 3 clinical trial of mifepristone (MIFE) for inoperable hypercortisolemia.

[0189]Prior to the start of MIFE, baseline urinary-free cortisol (UFC) was 2250 mcg / 24 hours (6207 nmol / 24 hours) and ACTH was 345 pg / mL (75.9 pmol / L). Late-night salivary cortisol (1.71 mcg / dL (47.2 nmol / L)) and serum cortisol (46 mcg / dL (1256 nmol / L)) were also elevated (Table 1). At the time of enrollment, the patient had overtly cushingoid...

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